Tissue-specific defects are caused by loss of the Drosophila MAN1 LEM domain protein

The nuclear lamina represents a protein network required for nuclear structure and function. One family of lamina proteins is defined by an ~40 aa LEM domain (LEM-D) that binds the non-specific DNA binding protein, Barrier-to-Autointegration Factor (BAF). Through interactions with BAF, LEM-D proteins serve as a bridge between chromosomes and the nuclear envelope. Mutations in genes encoding LEM-D proteins cause human laminopathies that are associated with tissue-restricted pathologies. Drosophila has five genes that encode proteins with LEM homology. Using yeast two hybrid analyses, we demonstrate that four encode proteins that bind Drosophila (d) BAF. In addition to dBAF, dMAN1 associates with lamins, the LEM-D protein Bocksbeutel and the receptor regulated Smads, demonstrating parallel protein interactions with vertebrate homologues. P element mobilization was used to generate null dMAN1 alleles. These mutants showed decreased viability, with surviving adults displaying male sterility, decreased female fertility, wing patterning and positioning defects, flightlessness and locomotion difficulties that became more severe with age. Increased phospho-Smad staining in dMAN1 mutant wing discs is consistent with a role in TGF-/BMP signaling. The tissue-specific, age enhanced dMAN1 mutant phenotypes are reminiscent of human laminopathies, suggesting that studies in Drosophila will provide insights into lamina dysfunction associated with disease.

Key Words: Emery Dreifuss Muscular Dystrophy, LEM domain, gene expression, nuclear lamina, nuclear organization

Online ISS 1091-6490
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